Certain n-substituted scopolammonium compounds

ABSTRACT

The specification describes new quaternary bromides of scopolamine in which the substituent on the nitrogen atom has the formula -(CH2)n-R in which R represents a cycloalkyl group containing up to six carbon atoms, an alkyl-substituted cycloalkyl group containing up to six carbon atoms or an epoxyethyl group and n is 1 or 2. Such compounds have valuable spasmolytic and anti-ulcer properties and pharmaceutical preparations containing them are also described.

United States Patent [191 Casadio et al.

[ CERTAIN N-SUBSTITUTEI) SCOPOLAMMONIUM COMPOUNDS [75] Inventors: Silvano Casadio; Arturo Donetti,

both of Milan, Italy [73] Assignee: Instituto De Angeli S.p.A, Milan,

Italy 22 Filed: Apr. 13, 1973 21 Appl.No.:350,927

[30] Foreign Application Priority Data Apr. I8, 1972 Great Britain 17920/72 [52] US. Cl. 260/292, 424/265 [51] Int. Cl C07d 43/06 [58] Field of Search .Q 260/292 [56] References Cited FOREIGN PATENTS OR APPLICATIONS 1,176,049 1/1970 Great Britain 260/292 Dec. 10, 1974 Primary ExaminerAlan L. Rotman Attorney, Agent, or Firm -Stewart & Kolasch, Ltd.

[5 7] ABSTRACT 7 Claims, No Drawings CERTAIN N-SUBSTITUTED SCOPOLAMMONIUM COMPOUNDS in which R represents a cycloalkyl, alkyl-substituted cycloalkyl or an epoxyethyl group, and n is an integer which may be 1 or 2.

In compounds of formula (I) in which R is a cycloalkyl or an alkyl-substituted cycloalkyl group such groups may contain up to 6 carbon atoms and preferably are a cyclopropyl, cyclobutyl or a methylcyclopropyl group.

The new compounds according to the invention have valuable spasmolytic and anti-ulcer properties as shown in detail hereinafter.

According to another feature of the invention, there is further provided a process for the preparation of compounds of formula (I) which comprises reacting scopolamine, as the free base, with a bromide of formula:

in which R is as above specified to effect quatemization. The reaction is preferably carried out in a polar inert solvent or, if desired, in an excess of the bromide of formula (II) and at a temperature ranging from room temperature to the reflux temperature of the reaction medium, preferably between and 100C. It will be appreciated that the reaction time may vary depending on the solvent and the reaction temperature. Thus acetonitrile is advantageously used as a solventthe temperature being kept at the reflux temperature of the reaction mixture.

According to a preferred manner of performing the reaction, 1 mole of scopolamine, free base, dissolved in acetonitrile, is refluxed with an excess of the bromide of formula (ll) (from 1.1 to 2 moles), for a period from 10 to 100 hours. The quaternary salt so obtained may then be isolated by cooling the reaction mixture and filtering, by suction, the crystalline solid that separates or, if the quaternary salt is so soluble as not to crystallize from the reaction medium, by evaporating the solvent under reduced pressure, the residue so obtained being then dissolved in water, the solution filteredfon charcoal, washed with ethyl ether and the solution evaporated to dryness and preferably lyophilized, to give the quaternary salt.

It will be appreciated that the main reaction may be accompanied by a side-reaction namely dehydrohalogenation which results in to the formation of scopolamine hydrobromide so that the separation of the pure quaternary salt may be difficult.

We have now found that, in such cases, a pure product can be isolated in a practical and easy way by treating the reaction mixture with ethylene oxide, which reacts with scopolarnine hydrobromide to give scopolamine free base and ethylene bromohydrin, both compounds being easily separable from the quaternary salt.

According to a preferred manner of effecting this purification, the reaction mixture, after completing the reaction, is cooled at room temperature, treated with an excess of ethylene oxide and left standing for 50-250 hours at OlOC. The solvent and the excess of ethylene oxide are then removed under reduced pressure and at a low temperature and the residue so obtained is dissolved in water, thoroughly washed with ether to remove the scopolamine base and the ethylene bromohydrin formed, and finally evaporated to dryness(preferably lyophilized.)

The compounds of formula (I) are colourless crystalline solids, when obtained by crystallization, or white amorphous solids, when obtained by lyophilization. They are soluble in water, methyl and ethyl alcohol, acetonitrile, dimethylformamide and practically insoluble in acetone, ether, dioxane and hydrocarbon solvents.

As stated above, the compounds according to the invention have valuable spasmolytic and anti-ulcer properties, coupled with a relatively low toxicity.

Preferred compounds for their useful properties are scopolamine-N(cyclopropyl-methyl) bromide, scopolamine-N-(cyclobutyl-methyl) bromide, scopolamine- N-(2-methyl-cyclopropyl-methyl)-bromide. A particularly preferred compound is scopolamine-N-(cyclopropyl-methyl)-bromide.

The properties of the new compounds may be illustrated by the results of the following experiments.

ACUTE TOXICITY Acute toxicity in mice by intraperitoneal route. LD have been calculated after 7 days of observation from the treatment according to Litchfield J. J. and Wilcoxon F., J. Pharm. Exp. Then, 96, 99 (1949) SPASMOLYT'IC ACTIVITY Spasmolytic activity on guinea pig ileum in vitro stimulated by acetylcholine (l.l0"' g/ml) and by BaCl (1.10 g/ml) according to Turba C. and Marazzi- ANTI-ULCER ACTIVITY Action on Shay ulcer in rats by intraduodenal route according to Shay H., Komarov S. A., Fels S. 8., Meranze D., Gruenstein M. and Siplet II, Gastroenterology, 5, 43-61 (1945).

Action on gastric secretion in rats after intraduodenal administration according to Birnbaum D., Medicina Psicosomatica, 13, l-4 (1968).

The above experiments have been carried out in The compositions are preferably formulated as doscomparison with scopolamine bromobutylate as referage units adapted to supply a single dose of the active ence. The results are shown in the following table and ingredient. Each dosage unit may conveniently contain are expressed on the basis of the activity of scopolafrom 1 I 100 g and preferably from 2.5 to mg of mine bromobutylate being equal to i. 5 po of formula Pharmacological Tests Dose opt-3177 opt-3235 opt-3236 DA-3237 opt-3245 Reference mg/Kg Scopola Scopola Scopola Soopola Scopola Sco la mme-N- mine-N- mine-N- mine-N- mine-N- mine somo (cyclo- (Z-methyl (cyclo- (cyclo- (2,3-epo butylate protgylcyclopro prop lbutylxy prome yl) pyl-meethy methyl) pyl)- bromide thyl)- bromide bromide bromide bromide Acute toxicity (in mice) LD ip. 0.6 e 0.8 1.3 0.8 0.7 l

Spasmolytic activity on Guineapig ileum in vitro stimulated by: acetylcholine (1.10") ED g/ml 3.l 2.9 2.6 2.7 1.4 l BaCl (1.10) ED g/ml 1.8 L0 0.8 0.8 0.1 l

Spasmolytic activity on Guinea pig gall-bladder in vitro stimulated by: acetylcholine (LlO ED g/ml 4.1 4 4.6 5.1 2.1 1

Spasmolytic activit in vivo on rabbit choledoc oduodenal junction stimulated b ncostigmine (60 mcgyKg i.v.): '71 increase of flux l0mcg/Kg 0.9 0.8 0.9 1.2 0.4 1

Action on Shay ulcer in rats: 71 of animals protected from ulcer 100 i.cl. 1.5 2 2 2 1.5 1

Action on gastric secretion in rats: inhibition 70 of the gastric juice 40 i.d. l 0.8 1.1 1.2 1.4 l

The above data show that the compounds of the in- As stated above, the pharmaceutical compositions vention have valuable spasmolytic and anti-ulcer propaccording to the invention may contain other active inerties, the spasmolytic properties mostly depending on gredients in addition to the compound of formula (1). their anti-cholinergic activity (inhibition of the action Particularly useful combination products include, for of acetylcholine). In particular DA-3 177, DA-3235 example, combination with analgesics (such as metamiand DA-3237, taking into account the relevant toxicitzole and d-propoxyphene), analgesic-sedatives (such as ies, have higher activities than the reference comcodeine salts and barbiturates), minor tranquilizers of pound. the benzodiazepines class, anti-ulcer drugs (such as ge- According to afurther feature of the invention, there famate), anti-emetlfis and f Sickness drugs are also provided pharmaceutical compositions com- Such as pfomethazme- The following examples are prising one or more compounds of formula (1} alone given merely as illustrative of the present invention and or in combination with other active ingredients 7 and are not to be consldered as hmmng' suitable excipients or carriers. The compositions may I 7 EXAMPLE 1 be presented in forms suitable for oral, parenteral or 19.67 g (0.065 moles) of scopolamine base and 17.6 rectal administration. g (0.13 moles) of cyclopropyl-methyl bromide are dis- Thus, for example, compositions for oral administra- 5O solved in acetonitrile and the solution is refluxed for 27 tion may be tablets, dragees, pills or capsules. Suitable hours. After cooling the reaction mixture scopolamineexcipients include lactose, sugar, starches (particularly N-( cyclopropyl-methyl)-bromide crystallizes and, after corn, maize and soluble starches), talc and/or magnefiltering, it is recrystallized from acetonitrile (mp.

sium stearate. .l ]o

Compositions for parenteral administration prefera- (C,3% in Hhd 20) bly consist of injectable solutions in a sterile carrier =l8.3

Analysis found C 57.46 H 6.45 N 3.24 Br 18.28 for C H BrNO calc 57.54 6.44 3.t9 18.23

preferably aqueous solutions. Such compositions are 1 EXAMPLE 2 I conveniently contained in vials.

In compositions for rectal administration the carrier 11.65 g (0.038 moles) of scopolamine base and 10.9

is preferably a conventional suppository base, for exg (0.073 moles) of cyclopropyl-ethyl-bromide are disample, a semi-synthetic glyceride. solved in ml of acetonitrile and the solution is refluxed for 99 hours. After cooling 4.82 g (0.11 moles) of ethylene oxide is added and then the reaction mixture is placed in an ice-box for 67 hours. After evaporating under reduced pressure the residue so obtained is dissolved in 150 ml of water and the solution is thoroughly washed with ether. The aqueous solution is lyophilized and scopolamine-N-(cyclopropyl-ethyl) bromide is obtained.

6 EXAMPLE 4 Hard gelatine capsules Scopolamine-Ntcyclopropyl-methyl )-bromide l0 mg lactose 89 do. talc l do.

The ingredients are intimately mixed and pulverized,

and the mixture is filled into hard gelatine capsules (C,3% in H 0) (0.100 g per capsule). Each capsule therefore contains 3l.9) 0.010 g of active substance.

Analysis found% C 57.73 H 6.73 N 3.05 Br 17.32 for C l-l BrNm 1 calc% 58.41 6.68 3.09 l7.66

The following quaternary salts are obtained in an anal- EXAMPLE 5 Ogous manner: Coated tablets Scopolamine-N-(2-methyl-cyclopropyl-methyl)- bromide I bSr (:)(r)'pi%l:nune-N-(cyclopropyl-methyl)- 10 mg reaction time with ethylene oxide: 236 hours lactose. talc and sugar. corn q.s. to 200 mg mp. 76-78C, [11],, Starch (C,3% 1n H O) The active compound, the excipients'and one half of o 12.8 the talc are intimately mixed. The m1xture 1s com- Analysis found% C 57.70 H 6.64 N 3.08 Br 17.76 for C H BrNO calc% 58.41 6.68 3.09 17.66

Scopolamine-N-(cyclobutyl-methyl)-bromide reaction time with ethylene oxide: 225 hours m.p. 7678C, [0:1

(C,3% in H O) pressed into pellets which are then granulated. The remaining talc is added to the granulate which is then compressed into tablets. The obtained tablets are coated with sugar and formed into coated tablets ac- 9 40 cording to conventional techniques. Each coated tab- Analysis found% C 57.85 H 6.8l N 3.02 Br 17.41 for C H BrNO CHlC7r 58.41 6.68 3.09 17.66

EXAMPLE 3 let, containing 10 mg of active substance, weighs 200 pressure, the residue is dissolved in water. The solution is washed several times with ether and treated with charcoal. The aqueous solution is lyophilized and scopolamine-N-(2,3-epoxy propyl)-bromide is obtained (m.p. 73-75C),

EXAMPLE 6 Suppositories Scopolamine-N-(cyclopropyl-methyl)- l0 mg bromide semisynthetic glycerides q.s. to 1200 mg The semisynthetic glycerides are melted and the ac- 20(C,3% in H 0) tive substance is dispersed in them, the mass obtained [a] D 7.4 is filled into cold moulds to produce suppositories each Analysis 1 found% C 54.32 H 6.03 N 3.13 Br 17.85 for C H BrNQ 7 of which weighs 1200 each suppository contains l mg of active substance.

A solution of the active ingredient in distilled water is filtered through a sintered glass filter and then filled into vials of 1 ml or 5 ml volume. The vials are sterilized. Each vial contains or mg respectively of active substance.

EXAMPLE 8 Vials scopolamine-N-(cyclopropyl-methyl)-bromide 0.020 sodium l-phenyl-2,3-dirneth l-5-pyrazolone- -4-methylaminomethane sulp onate (Novalgin 2.5 distilled water q.s. to 5 The procedure is that of Example 7.

EXAMPLE 9 Suppositories scopolamine-N-(cyclo ropyl-methyl )-bromide 0.010 sodium l-phenyl-2,3- imeth l-5-pyrazolone -4-methylaminomethane sulp onate (Novalgm semisynthetic glycerides q.s. to

The procedure is that of Example 6.

EXAMPLE 1O Coated tablets sco lamine-N-(c clo ropyl-methyl)-bromide sodifm l-phenyl-2(3-dimethyl-5-pyrazolone- 4-methylaminomethane sulphonate (NOvalgin lactose, talc, sugar, corn starch q.s. to

The procedure is that of Example 5.

EXAMPLE 1 l Coated tablets scopolamine-N-( cyclopropyl-methyl )-bromide dpropoxyphene hydrochloride corn starch, talc, sugar lactose 10 mg 65 mg q.s. to 200 mg The procedure is that of Example 5.

EXAMPLE 12 Suppositories scopolamine-N-(cyclopropylmethyl)-bromide y d-propoxyphene hydrochloride semisynthetic glycerides q.s. to

The procedure is that of Example 6.

EXAMPLE 13 Soft elastic capsules scopolamine-N-tcyclopropylmethyl )-bromide geranyl farnesylacetate triglycerides of saturated vegetable fatty acids q.s. to

5 mg 50 mg 10mg 100 mg The active ingredients are added to the triglycerides of saturated vegetable fatty acids and the solution is encapsulated in soft elastic capsules consisting of 45% gelatine, 20% glycerol and 35% water. The capsules obtained (0.155 g or 0.310 g per capsule) are then dried at room temperature. Each capsule contains 55 mg or mg of active ingredients.

The procedure is that of Example 6.

Compounds of the invention can be made up into pharmaceutical compositions and preparations by conventional techniques some of which are illustrated by Examples 4 to 15.

We claim:

1. Ascopolamine derivative having the following general formula:

CH; CH

CH; O H CH; C H

OBrS CH wherein R represents a cycloalkyl group containing up to five carbon atoms, a lower alkyl-substituted cycloalkyl group containing up to six carbon atoms or an epoxyethyl group'and n is l or 2.

2. A scopolamine derivative according to claim 1, wherein R is a cyclopropyl, cyclobutyl or a methylsubstituted cyclopropyl group.

3. A compound according to claim 1 which is scopolamine-N-(cyclopropylmethyl) bromide.

4. A compound according to claim 1 which is scopolamine-N-(2-methyl-cyclopropylmethyl) bromide.

5. A compound according to claim 1 which is scopolamine-N-(cyclopropylethyl) bromide.

6. A compound according to claim 1 which is scopolamine-N-(cyclobutylmethyl) bromide.

7. A compound according to claim 1 which is scopolamine-N-(2,3 -epoxypropyl) bromide.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,853 ,886 Dated December 10 1974 Inventor(s) Silvano Casadio and Arturo Donetti It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the Heading of the Patent:

After Assignee, change "Institute" to- -Istituto- In the Specification:

Col 4, line 55, change "Hhd 20" to-H O-- Signed and Scaled this twenty-third Day Of September 1975 [SEAL] A ttes t:

RUTH C. MASON C. MARSHALL DANN N I IIX ffll ('mnmisxinm'r nj'lurcnts and Trademarks 

1. A SCOPOLAMINE DERIVATIVE HAVING THE FOLLOWING GENERAL FORMULA:
 2. A scopolamine derivative according to claim 1, wherein R is a cyclopropyl, cyclobutyl or a methyl-substituted cyclopropyl group.
 3. A compound according to claim 1 which is scopolamine-N-(cyclopropylmethyl) bromide.
 4. A compound according to claim 1 which is scopolamine-N-(2-methyl-cyclopropylmethyl) bromide.
 5. A compound according to claim 1 which is scopolamine-N-(cyclopropylethyl) bromide.
 6. A compound according to claim 1 which is scopolamine-N-(cyclobutylmethyl) bromide.
 7. A compound according to claim 1 which is scopolamine-N-(2,3-epoxypropyl) bromide. 